Reactive oxygen species

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ROS leake from mitochondrial metabolism

Mitochondria, among other important biosynthetic and catabolic functions like beta-oxidation, harbour the Krebs cycle (organic acid cycle, OAC) and respiratory chain (RC) membrane complexes. The latter are known to leake reactive oxygen species (ROS) during the processes conferring oxidative phosphorylation, which combines reduction of oxygen with the production of ATP.

ROS damage mitochondria and the cell

ROS have a high potential to cause mitochondrial and cellular damage to lipids, proteins and -most importantly- DNA. The mitochondrial DNA (mtDNA) is especially damaged due to it's proximity to the sites of ROS production.

ROS are discussed to play a role in aging and cancer.

Situation in mammals

cc9098-1.gif Bild:

Paper.svg Galley (2010)
Bench-to-bedside review: Targeting antioxidants to mitochondria in sepsis
PubMed (title) PubMed (ID) Google Vorlage:Paper

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Paper.svg McEwen et al (2011)
Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury
PubMed (title) PubMed (ID) Google Vorlage:Paper

Minimization of ROS production is a key driving force in mitochondrial evolution

Since mitochondria multiply inside the eucaryotic cell during the latter's life cycle, their evolution is more efficient than their host's. Thus, also the evolution of OAC and RC genes can be expected to be more efficient. This fact might, besides, also have an impact on which genes have moved or not moved to the nucleus during the co-evolution of cells and their mitochondria.

The production of ROS leads to mutations in mtDNA and primarily affects the mitochondrion producing them. On the one hand, by these means ROS facilitate mitochondrial gene diversity and thus have the potential to accelerate adaptations towards ROS tolerance and/or reduction of ROS production due to enhanced mitochondrial evolution. On the other hand, high concentrations of ROS can damage the mtDNA to an unrecoverable extent, leading to loss of mtDNA. Understandably, cells containing mtDNA-deficient "ghost" mitochondria, exhibit severe growth defects [1].

Mitochondrial quality needs to be controlled

Since ROS leake from Mitochondrial health have a high impact on the cellular health status and their quality must be ensured by strict control mechanisms. The nuclear DNA encodes a set of genes, which select mitochondria for quality controlled mitophagy. Since leakage of ROS in the RC diminish the mitochondrial membrane potential (delta Psi), it is senseful to couple mitochondrial selection to their individual energy output. In fact, a mechanism exists, labeling mitochondria according to their membrane potential (see below).

During carbon starvation we do not expect ROS production

On the other hand, during carbon source depletion (carbon starvation), the TCA and OP pathways can be expected to be inactive anyway, accordingly not producing ROS. Nevertheless yeast shows mitophagy in stationary phase, when all kinds of nutrients become limited including carbon sources. It is difficult to predict, whether mitophagy in stationary phase is rather due to nitrogen starvation or quality control. When energy becomes limited, the cells could decide to put additional selective pressure on their mitochondria, to confer, that the remaining nutrients are metabolized by the more efficient mitochondria. Also, the cells could expect not to need their mitochondria in the near future. Kanki et al report, that Atg33 was essential for mitophagy during stationary phase, which was attributed to mitochondrial quality control due to it's selective behaviour. These findings leave the question, whether Atg32 and Atg33 function parallel, upstream or downstream of each other.

ROS minimization extends lifespan up to one third

The importance of ROS minimization is underlined by the finding, that lifespan extension of yeast in delta sch9, delta cyr1 and delta ras2 mutants is confered by enhanced expression of the mitochondrial superoxide dismutase Sod2. Additionally, co-overexpression of Sod1 and Sod2 is capable of extending yeast lifespan up to 30%, which is attributed to increased protection of the ROS-susceptible mitochondrial aconitase. Yet, the question remains open, why given these findings, yeast is not increasing it's lifespan by up-regulating superoxide dismutase in the wild-type.

It is unresolved, how ROS are sensed in the cell

Peroxiredoxins, glutathione, ascorbate, glutaredoxins, thioredoxins, ferredoxin, NADPH as well as the mitochondrial aconitase itself have been proposed, to provide feedback about intracellular ROS levels.

However, ROS leakage may also be indirectly measured via the diminished mitochondrial membrane potential, and since we believe, that the latter can easily be directly coupled to energy-driven mitochondria-selection mechanisms in the cell, we will focus on this idea in the context of this work.

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